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Cmichael
Mechanisms of translational control in aging liver
Posted in Aging on Wed October 04, 2006
Gene expression changes dramatically over the course of aging. It’s relatively common to find a paper that addresses these alterations in gene expression (especially at the level of transcriptional regulation), but rare to find one that addresses the mechanism of the change. Which factors govern differential gene expression in the aged cell? We don’t know, and in the age of cheaper and cheaper microarrays and increasingly accessible mass-spec for protein expression studies, it seems like we rarely ask.
Hence I was pleased to see today’s paper. Timchenko et al. begin with a few established points of reference (known changes in gene expression and in levels of regulatory proteins) and proceed to systematically identify and characterize a multiprotein complex, involved in translational regulation, that is upregulated in the aged liver. Furthermore, they demonstrate that this complex determines differential translation of multiple isoforms of a broad-spectrum transcription factor:
RNA binding protein, CUGBP1, regulates translation of proteins in a variety of biological processes. In this paper, we show that aging liver increases CUGBP1 translational activities by an induction of a high molecular weight protein-protein complex of CUGBP1. The complex contains CUGBP1, subunits alpha, beta and gamma of the initiation translation factor eIF2 and four proteins of the endoplasmic reticulum, eR90, CRT, eR60 and Grp78. The induction of the CUGBP1-eIF2 complex in old livers is associated with the elevation of protein levels of CUGBP1 and with the hyper-phosphorylation of CUGBP1 by a cyclin D3-cdk4 kinase, activity of which is increased with age. … The CUGBP1-eIF2 complex is bound to C/EBP beta mRNA in the liver of old animals and this binding correlates with the increased amounts of LAP and LIP. Consistent with these observations, the purified CUGBP1-eIF2 complex binds to the 5’ region of C/EBP beta mRNA and significantly increases translation of the three isoforms of C/EBP beta in a cell-free translation system, in cultured cells and in the liver. Thus, these studies demonstrated that age-mediated induction of the CUGBP1-eIF2 complex changes translation of C/EBP beta in old livers.
CUGBP-1 was already known to be upregulated in senescent fibroblasts, where it increases translation of CDK inhibitor p21WAF1. LIP, the C/EBPß isoform whose levels rise, was already known to be upregulated in the aging liver. The novelty here is in mechanistically bridging the two observations, showing that both in vivo and in vitro, the upregulation of a multiprotein complex containing CUGBP-1 increases translation of this specific C/EBPß isoform.
LIP is a dominant negative whose expression presumably represses transcription of genes responsive to other C/EBPß isoforms; while the full ramifications of the upregulation of LIP await a detailed transcriptional study, but it’s reasonable to speculate that high LIP results in repression of liver-specific genes in an aged organ.
So I like this prelimiary story: A multiprotein complex specific to an aged tissue post-transcriptionally regulates a transcription factor, resulting (presumably) in a dramatic change in transcription throughout the genome. Granted that in one sense it simply pushes the question back one step further (why the upregulation of the CUGBP-1 complex?), it still provides refreshing dose of mechanism in a line of research that sometimes gets bogged down in the lepidopteristic listing of upregulated and downregulated genes.
One point of disgruntlement: The authors used mass spec to identify the subunits of their complex, and confirmed the identifications by Western blot. Strangley, several of the proteins (CUGBP-1 and the subunits of eIF2) are cytosolic — but several others (including Grp78 and calreticulin) live in the endoplasmic reticulum (ER). Now, the cytosol and the ER are separated by a membrane that takes some work to get across, so it’s hard to believe that the native complex actually includes all of these proteins. I would hazard to guess that the cell lysis conditions used here somehow violate the ER membrane and allow abundant chaperones to bind to the cytosolic “half” of the complex. The authors are curiously uncritical about their discovery of a multiprotein complex whose subunits reside in different membrane-bound compartments of the cell, failing to mention this issue even in passing.
Finally, a more general point on the study of gene expression in aging. A question unasked and therefore unanswered in this and many papers is what, if anything, age-related changes in gene expression signify: Are they deleterious, protective, passive responses to damage-induced signals, neutral, or other? It’s a gigantic question, far beyond the scope of any one paper. But since I introduced the discussion of the paper by talking about what I’d like to see more of in the field, it seems an appropriate way to end.
Happy Friday, everyone. Be good to your livers.
http://www.worldhealth.net/news/mechanisms...al_control_in_a
Obama White House Can Save $3.7 Trillion and Extend Lifespan 29+ Years,
Predicts Revolutionary A4M Healthcare Plan
Contributing Editors
Ronald M. Klatz, M.D., D.O., President & Physician Co-Founder, American Academy of Anti-Aging Medicine (A4M); Appointed member, Global Action Council on the Challenges of Gerontology, World Economic Forum; Director, World Anti-Aging Academy of Medicine
Robert M. Goldman, M.D., Ph.D., D.O., FAASP, Chairman & Physician Co-Founder, American Academy of Anti-Aging Medicine (A4M); World Chairman, International Medical Commission; Chairman, World Anti-Aging Academy of Medicine; President Emeritis, National Academy of Sports Medicine
Joseph C. Maroon, M.D., Professor of Neurosurgery, Heindl Scholar in Neuroscience and Vice Chairman of Neurosurgery, University of Pittsburgh Medical Center; Member of the International Editorial Board, Neurological Research and the Journal of Sports Medicine; Past President, Congress of Neurological Surgeons
Nicholas A. DiNubile, M.D., Orthopaedic Consultant to the Philadelphia 76ers Basketball Team and Pennsylvania Ballet
Michael Klentze, M.D., Ph.D., Secretary-General, European Society of Anti-Aging Medicine; Medical Director, Vitalife Wellness Center of Bumrungrad Hospital, Thailand
The American Academy of Anti-Aging Medicine (A4M; www.worldhealth.net), the world's largest professional organization dedicated to advancing research and clinical pursuits that enhance the quality, and extend the quantity, of the human lifespan. unveils an innovative, technology-based fix to healthcare with the potential to:
• Increase the lifespan, or improve the healthspan, of all Americans by 29+ years;
• Slash healthcare costs, saving $3.7 Trillion; and
• Replace the disease-based approach to medicine with a wellness-oriented model
A comprehensive program to reform and advance healthcare in the United States, The A4M Twelve-Point Actionable Healthcare Plan: A Blueprint for A Low Cost, High Yield Wellness Model of Healthcare by 2012 has garnered support from 35 professional medical organizations and educational institutions and was developed with invaluable input from the 24,000 physician, health practitioner, and scientist members of the American Academy of Anti-Aging Medicine (A4M; www.worldhealth.net) who represent 110 nations worldwide.
When legislators on Capitol Hill return for the Fall Congress Session, they will continue to debate a $1.65 trillion, 10-year plan to overhaul the nation’s failing healthcare system. The majority of the plan focuses on how to pay for health insurance, rather than formulating a comprehensive plan of action for reform itself. The contributing editors, authors and endorsing organizations of The Twelve-Point Plan submit that the underlying philosophy of healthcare in this nation must be reformed in revolutionary new ways. In place of the disease-based approach that treats people after they exhibit signs of illness, we submit that it is time for the nation to adopt a wellness-oriented model to healthcare. Such a model stresses very early detection of illness and promotes disease prevention, yielding opportunities for the best prognoses and economical treatments. As reported by the Congressional Budget Office, up to one-third of this nation’s healthcare spending -- more than $700 billion -- does not improve Americans' health outcomes.
To compound the issue of healthcare reform, the United States is a driving force in a trend of unprecedented global aging. The average age of the world's population is increasing at an unprecedented rate. The number of people worldwide ages 65+ was 506 million as of midyear 2008; by 2040, that number will hit 1.3 billion. Thus, in just over 30 years, the proportion of older people will double from 7% to 14% of the total world population. In the United States, men and women ages 65+ represented 12.4% of the population in the year 2000, with that age bracket projected to swell to stand at 20% of the population by 2030. In 2007 in the United States, six major diseases among Americans ages 65+ resulted in medical and lost productivity costs of more than $196 billion. In the coming years, the cases of these six diseases, namely -- chronic lung disease, ischemic heart disease, stroke, lung cancer, pneumonia and gastrointestinal illness -- are expected to surge as the population ages, potentially sending the costs of age-related diseases skyrocketing. Steps to prepare the nation to address the social, economic, and personal ramifications of a graying society now, are urgently necessary.
Anti-aging medicine is the pinnacle of biotechnology joined with advanced clinical preventive medicine. Adoption of the anti-aging medical model delivers the best of advanced preventive medicine to all Americans, not merely our older population segments. The contributing editors, authors and endorsing organizations of The Twelve-Point Plan urge this nation to adopt a wellness-oriented model to healthcare.
The elements of The Twelve-Point Plan will significantly improve and extend the healthy human lifespan. Each of the points of this Program will also deliver a profound net economic savings via three major mechanisms:
1. Conservation of worker productivity
2. Reduction of disability and hospitalization costs
3. Reduction of the burden of costs associated with chronic long-term medical conditions.
The Twelve-Point Plan provides practicable “here and now” solutions to reform and advance healthcare in the United States, while addressing the challenges of global aging. Indeed, the implementation of The A4M Twelve-Point Actionable Healthcare Plan: A Blueprint for A Low Cost, High Yield Wellness Model of Healthcare by 2012 may save our society a projected $3.64 Trillion in healthcare costs, and extend the healthy lifespan of each of our nation’s residents by up to 29 productive, vital years.
Complete references and supporting data for projections may be viewed in the full version of The A4M Twelve-Point Actionable Healthcare Plan: A Blueprint for A Low Cost, High Yield Wellness Model of Healthcare by 2012. Request your free copy of this White Paper, at: www.waaam.org/twelve_points_summary.php.
for more information , visit here :
http://www.worldhealth.net
